Tazopenil

PACKAGE LEAFLET: INFORMATION FOR THE USER

TAZOPENIL 2 g/0,25 g/4 ml powder and solvent for injectable solution for intramuscular use
TAZOPENIL 4 g/0,5 g powder for solution for infusion
Piperacillin / tazobactam
Generic medicine
Please read all of this leaflet carefully before you start using this medicine, as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if they have the same symptoms as you, because it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

What this leaflet contains:

1. 1. What TAZOPENIL is and what it is used for
2. 2. What you need to know before using TAZOPENIL
3. 3. How to use TAZOPENIL
4. 4. Possible side effects
5. 5. How to store TAZOPENIL
6. 6. Contents of the pack and other information

1. WHAT TAZOPENIL IS AND WHAT IT IS USED FOR

Piperacillin belongs to a group of medicines known as "broad-spectrum penicillin antibiotics" and is able to kill many types of bacteria. Tazobactam can prevent certain resistant bacteria from surviving the effects of piperacillin. This means that when piperacillin and tazobactam are given together, they can kill a wider range of bacteria.

TAZOPENIL is used in adults and adolescents to treat bacterial infections such as those affecting the lower respiratory tract (lungs) or urinary tract (kidneys and bladder), as well as infections of the abdomen, skin, or blood. TAZOPENIL may be used to treat bacterial infections in patients with low white blood cell counts (reduced resistance to infections).

TAZOPENIL is used in children aged 2 to 12 years for the treatment of abdominal infections such as appendicitis, peritonitis (infection of the fluid and tissue lining the abdominal organs), and gallbladder (biliary) infections. TAZOPENIL may be used to treat bacterial infections in patients with low white blood cell counts (reduced resistance to infections).

In certain severe infections, your doctor may consider using TAZOPENIL in combination with other antibiotics.

2. WHAT YOU SHOULD KNOW BEFORE USING TAZOPENIL

DO NOT USE TAZOPENIL

• If you are allergic to piperacillin, tazobactam, lidocaine, or any of the other ingredients of this medicine (listed in section 6);
• If you are allergic to antibiotics known as penicillins, cephalosporins, or other beta-lactamase inhibitors, as you may also be allergic to TAZOPENIL;

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Tazopenil:

• If you have allergies. If you have multiple allergies, inform your doctor, pharmacist, or nurse before taking this medicine;
• If you have diarrhoea before treatment or if you develop diarrhoea during or after treatment. In this case, you must inform your doctor, pharmacist, or nurse immediately. Do not take medicines for diarrhoea without first consulting your doctor;
• If you have low levels of potassium in your blood. Your doctor may decide to check your kidney function before administering this medicine and may prescribe periodic blood tests during treatment;
• If you have kidney or liver problems or if you are undergoing haemodialysis. Your doctor may decide to check your kidney function before administering this medicine and may prescribe periodic blood tests during treatment;
• If you are taking another antibiotic called vancomycin. Taking Tazopenil and vancomycin together may increase the risk of kidney damage (see also section “Other medicines and Tazopenil” in this leaflet);
• If you are taking certain medicines (called anticoagulants) to prevent excessive blood clotting (see also section “Other medicines and Tazopenil”), or if unexpected bleeding occurs during treatment. In this case, you must inform your doctor, pharmacist, or nurse immediately;
• If you develop seizures during treatment. In this case, you must inform your doctor, pharmacist, or nurse immediately;
• If you think you have developed a new infection or if your infection has worsened. In this case, you must inform your doctor, pharmacist, or nurse.

Haemophagocytic lymphohistiocytosis
Cases of a condition in which the immune system produces an abnormally high number of white blood cells called histiocytes and lymphocytes, leading to inflammation (haemophagocytic lymphohistiocytosis), have been reported. This condition can be life-threatening if not diagnosed and treated early.
If you develop several symptoms such as fever, swollen lymph nodes, feeling of weakness, mental confusion, shortness of breath, bruising, or skin rash, contact your doctor immediately.
If you notice muscle pain, tenderness, or weakness and/or dark-coloured urine, inform your doctor immediately, as treatment will be stopped, since these symptoms could be signs of muscle breakdown (rhabdomyolysis), which can lead to kidney problems.

Children
The use of Tazopenil is not recommended in children under 2 years of age due to insufficient data on safety and efficacy.

Other medicines and Tazopenil
Tell your doctor, pharmacist, or nurse if you are taking, have recently taken, or might take or need to take any other medicines, including those without a prescription.
Some medicines can interact with piperacillin and tazobactam. These include:

• Medicines for gout (probenecid). These may increase the time required for elimination of piperacillin and tazobactam from the body;
• Medicines to thin the blood or treat blood clots (e.g. heparin, warfarin, or aspirin);
• Medicines used to relax muscles during surgery. Inform your doctor if you are undergoing general anaesthesia;
• Methotrexate (a medicine used to treat cancer, arthritis, or psoriasis).
  Piperacillin and tazobactam may increase the time required for elimination of methotrexate from the body;
• Medicines that can reduce potassium levels in the blood (e.g. tablets that increase urine production or certain cancer medicines);
• Medicines containing other antibiotics such as tobramycin, gentamicin, or vancomycin. Inform your doctor if you have kidney problems. Taking Tazopenil and vancomycin together may cause acute kidney damage, even if you do not have pre-existing kidney problems.

Effect on laboratory tests
Inform your doctor or laboratory staff that you are taking TAZOPENIL if you are required to provide a blood or urine sample.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or breastfeeding, consult your doctor, pharmacist, or nurse before using this medicine.
Your doctor will decide whether TAZOPENIL is suitable for you.
Piperacillin and tazobactam may pass to the unborn child through the placenta or pass into breast milk.
If you are breastfeeding, your doctor will decide whether TAZOPENIL is suitable for you.

Driving and using machines
TAZOPENIL is not expected to affect your ability to drive or use machinery.

TAZOPENIL contains sodium
TAZOPENIL 2 g/0.25 g/4 ml contains 108 mg of sodium.
This corresponds to 5.4% of the maximum daily recommended dietary intake for an adult.
TAZOPENIL 4 g/0.5 g contains 216 mg of sodium.
This corresponds to 10.8% of the maximum daily recommended dietary intake for an adult.
This should be taken into account in individuals with impaired kidney function or those on a low-sodium diet.

3. HOW TO USE TAZOPENIL

Use this medicine exactly as instructed by your doctor, pharmacist, or nurse. If you have any doubts, consult your doctor, pharmacist, or nurse.
TAZOPENIL 2 g/0,25 g may be administered either by intramuscular route or by slow intravenous injection (lasting at least 3–5 minutes) or by infusion (a 30-minute intravenous drip) into a vein.
The vial of solvent containing lidocaine, included in the TAZOPENIL 2 g/0,25 g/4 ml pack, must be used exclusively for intramuscular administration.
TAZOPENIL 4 g/0,5 g may only be administered by slow intravenous injection or by infusion (a 30-minute intravenous drip) into a vein.
Your doctor or another healthcare professional will administer this medicine to you via infusion (a 30-minute intravenous drip) into a vein.

Dosage
The dose of medicine you will receive depends on the condition being treated, your age, and whether you have kidney problems.

Adults and adolescents over 12 years of age
TAZOPENIL 2 g/0,25 g/4 ml powder and solvent for injectable solution for intramuscular use
The usual dose for adults and adolescents aged 12 years and older with normal kidney function is 2 g/0,25 g of piperacillin and tazobactam every 12 hours up to every 6 hours, administered by intramuscular injection.

TAZOPENIL 4 g/0,5 g powder for infusion solution
The usual dose is 4 g/0,5 g of piperacillin/tazobactam administered every 6–8 hours into a vein (directly into the bloodstream).

Children aged between 2 and 12 years
The usual dose for children with abdominal infections is 100 mg/12.5 mg/kg body weight of piperacillin/tazobactam, administered every 8 hours into a vein (directly into the bloodstream).
The usual dose for children with low white blood cell counts is 80 mg/10 mg/kg body weight of piperacillin/tazobactam every 6 hours, administered intravenously (directly into the bloodstream).
The doctor will calculate the dose based on the child's body weight; however, no individual dose will exceed 4 g/0.5 g of TAZOPENIL.

TAZOPENIL should be used until all signs of infection have completely disappeared (from 5 to 14 days). The duration of treatment should be determined according to your doctor's instructions. If you have any doubts about how to use this medicine, consult your doctor.
For instructions on use and proper reconstitution, see the section “The following information is intended exclusively for doctors or healthcare professionals” at the end.

Patients with kidney problems
Your doctor may need to reduce the dose of TAZOPENIL or the frequency of administration. Your doctor may also perform blood tests to ensure that the prescribed dose is appropriate, especially if you are to take this medicine for a prolonged period.

If you use more TAZOPENIL than you should
If you think you have used or have been given too much medicine, or if you experience adverse effects such as seizures, inform your doctor immediately.

If you forget to use TAZOPENIL
If you think a dose of TAZOPENIL has not been administered or you have missed a dose, inform your doctor, pharmacist, or nurse immediately.

If you have any doubts about using this medicine, consult your doctor or nurse.

4. POSSIBLE ADVERSE REACTIONS

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences them.
Seek immediate medical advice if you experience any of the following potentially serious adverse reactions associated with Tazopenil:
Serious adverse reactions of Tazopenil include:

• severe skin rashes (Stevens-Johnson syndrome, bullous dermatitis, and toxic epidermal necrolysis), which initially appear as reddish spots or circular raised areas, often with central blisters, on the trunk. Further symptoms include ulcers in the mouth, throat, nose, extremities, genitals, and conjunctivitis (red and swollen eyes). The skin rash may progress to widespread blistering or peeling of the skin, which can potentially be life-threatening; severe skin inflammation leading to extensive skin peeling (exfoliative dermatitis);
• a severe, potentially fatal allergic condition (drug reaction with eosinophilia and systemic symptoms) that may affect the skin and, particularly, other internal organs such as the kidneys and liver;
• a skin condition (generalized acute exanthematous pustulosis) accompanied by fever, characterized by numerous small, fluid-filled pustules within large areas of swollen and reddened skin;
• swelling of the face, lips, tongue, or other body parts;
• shortness of breath, wheezing, or difficulty breathing;
• sudden chest pain, which may occur during an allergic reaction known as Kounis syndrome;
• severe rash, itching, or hives on the skin;
• yellowing of the eyes or skin;
• damage to blood cells (signs include: unexpected shortness of breath, red or brown urine, nosebleeds, appearance of bruising), pinpoint hemorrhages, severe reduction in white blood cell count;
• severe or persistent diarrhea accompanied by fever or weakness;
• muscle pain, tenderness, or weakness and/or dark-colored urine (rhabdomyolysis, frequency not known).

Other adverse reactions:
Very common adverse reactions (may affect more than 1 in 10 people):

• diarrhea

Common adverse reactions (may affect up to 1 in 10 people):

• fungal infection (e.g., candidiasis);
• reduced platelet count, reduced red blood cell count or blood pigment/hemoglobin, abnormal laboratory test (positive direct Coombs test), prolonged bleeding time (prolonged activated partial thromboplastin time);
• decreased albumin protein in the blood, decreased total blood protein levels;
• headache, insomnia;
• abdominal pain, vomiting, nausea, indigestion, stomach discomfort;
• increased levels of certain enzymes in the blood (alkaline phosphatase, increased alanine aminotransferase, increased aspartate aminotransferase);
• skin rash, itching;
• abnormal blood tests for kidney function (increased blood creatinine);
• fever, injection site reaction.

Uncommon adverse reactions (may affect up to 1 in 100 people):

• reduced white blood cell count (leukopenia), prolonged blood clotting time (prolonged prothrombin time);
• low potassium levels in the blood (hypokalemia), low blood sugar (glucose);
• seizures, reported in patients receiving high doses or with kidney problems;
• low blood pressure, inflammation of veins (felt as tenderness or redness in the affected area);
• flushed, reddened skin with hot flashes;
• increased levels of pigment breakdown products in the blood (bilirubin);
• skin reactions with redness and skin lesions (rash, erythema multiforme);
• hives;
• joint and muscle pain;
• chills.

Rare adverse reactions (may affect up to 1 in 1,000 people):

• severe reduction in granular white blood cells (agranulocytosis), nosebleeds;
• serious colon infection;
• inflammation of the mucous membranes in the mouth;
• detachment of the upper layer of skin over the entire body (toxic epidermal necrolysis).

Frequency not known (frequency cannot be estimated from available data):

• severe reduction in red blood cells, white blood cells, and platelets (pancytopenia), reduced white blood cells (neutropenia), reduced red blood cells due to premature destruction (hemolytic anemia), appearance of bruising with small spots (purpura), prolonged bleeding time;
• increased platelet count, increased levels of a specific type of white blood cell (eosinophilia);
• severe allergic reaction;
• jaundice (yellowing of the skin or whites of the eyes);
• severe, widespread allergic reaction affecting the entire body with skin and mucosal rash and various skin eruptions (Stevens-Johnson syndrome), severe allergic reaction involving the skin and other internal organs such as the kidneys and liver (drug reaction with eosinophilia and systemic symptoms), numerous small fluid-filled pustules within large areas of swollen and reddened skin accompanied by fever (generalized acute exanthematous pustulosis);
• skin reactions with blisters (bullous dermatitis);
• reduced kidney function and kidney problems;
• accumulation of eosinophils, a type of white blood cell, in the lungs (eosinophilic pneumonia);
• acute disorientation and confusion (delirium).

Treatment with piperacillin has been associated with a higher incidence of fever and skin rashes in patients with cystic fibrosis.
Beta-lactam antibiotics, including piperacillin/tazobactam, may lead to manifestations of signs of impaired brain function (encephalopathy) and seizures.

Reporting of adverse reactions
If you experience any adverse reaction, including those not listed in this leaflet, consult your doctor, pharmacist, or nurse. You may also report adverse reactions directly via the national reporting system at www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting adverse reactions, you can help provide more information on the safety of this medicine.

5. HOW TO STORE TAZOPENIL

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and vial after "Exp.".
The expiry date refers to the last day of that month.
Intact vials: do not store above 25°C.
For single use only.
Reconstituted solution: after reconstitution, the solution should be administered immediately.
Discard any unused solution.
Do not dispose of medicines via wastewater or household waste.
Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. PACKAGING CONTENTS AND OTHER INFORMATION

What TAZOPENIL contains

• The active substances are piperacillin (as sodium salt) and tazobactam (as sodium salt).

TAZOPENIL 2 g/0.25 g/4 ml powder and solvent for injectable solution for intramuscular use
Each vial contains 2 g of piperacillin (as sodium salt) and 0.25 g of tazobactam (as sodium salt).
The solvent ampoule contains: lidocaine hydrochloride, water for injections.
TAZOPENIL 4 g/0.5 g powder for solution for infusion
Each vial contains 4 g of piperacillin (as sodium salt) and 0.5 g of tazobactam (as sodium salt).

Description of the appearance of TAZOPENIL and contents of the pack
TAZOPENIL 2 g/0.25 g is a white to off-white powder supplied in a vial.
The pack contains 1 vial of powder and 1 ampoule of solvent containing lidocaine hydrochloride 20 mg/ml.
(The solvent ampoule containing lidocaine hydrochloride is for intramuscular use only.)
TAZOPENIL 4 g/0.5 g is a white to off-white powder supplied in a vial.
The pack contains 1 vial.
Not all pack sizes may be marketed.

Marketing Authorization Holder
Aesculapius Farmaceutici S.r.l. - Via Cefalonia, 70 - 25124 Brescia
Manufacturer
Mitim S.r.l. – Via Cacciamali 34-36-38 – 25125 Brescia

The following information is intended for healthcare professionals only.
Instructions for use
A. Intramuscular use
TAZOPENIL 2 g / 0.25 g must be reconstituted with the solvent ampoule provided in the pack, containing
4 ml of a 0.5% lidocaine solution.
The solvent ampoule containing lidocaine supplied with the pack must only be used for intramuscular administration.
Do not exceed a dose of 2 g / 0.25 g of piperacillin/tazobactam per injection site.
For correct reconstitution, follow the procedure below:

1. Shake the vial to loosen the powder from the bottom of the vial.
2. Remove the flip-off plastic cap from the vial to expose the central portion of the rubber stopper and keep it aside (Fig. 1). Always avoid touching the central portion of the rubber stopper with hands.

3. Using a syringe, withdraw the solvent from the ampoule and transfer it into the vial containing the powder.
4. Place the plastic cap back onto the rubber stopper to prevent touching the central portion with fingers. Shake vigorously until the powder is completely dissolved. Under constant agitation, reconstitution should be completed within 10 minutes (Fig. 2).

5. Let the resulting solution stand until foam disappears and a clear solution is obtained. Ensure that no undissolved particles remain.
6. Remove the plastic cap and withdraw the solution using a 5 ml syringe for intramuscular administration.
7. Inject the reconstituted solution deeply into a muscle.

After reconstitution, the solution must be administered immediately.
Unused solutions must be discarded.

B. Intravenous use
Reconstitute each vial with the volume of solvent indicated in the table below, using one of the compatible solvents listed.
Rotate gently until the powder is completely dissolved. With constant rotation, reconstitution generally takes between 5 and 10 minutes (for further information on handling, see below).

*Compatible solvents for reconstitution:

• Sterile water for injectable preparations
• 0.9% sodium chloride injectable solution (9 mg/ml)
• 5% glucose

Shake the vial containing the powder to be reconstituted to detach the powder from the bottom of the vial.
Using a syringe, withdraw an appropriate solvent and introduce it into the vial containing the powder.
Shake vigorously until the powder is completely dissolved. With continuous agitation, reconstitution should be complete within 10 minutes.
Allow the resulting solution to stand until foam disappears and a clear solution is obtained. Ensure that no undissolved particles remain before withdrawing with a suitable syringe.
The reconstituted solution must be withdrawn from the vial using a syringe. Once reconstituted according to instructions, the contents withdrawn with the syringe will provide the amount of piperacillin and tazobactam stated on the label.
Reconstituted solutions may be further diluted to the desired volume (e.g., from 50 to 150 ml) with one of the following compatible solvents:

• Sterile water for injectable preparations
• 0.9% sodium chloride injectable solution (9 mg/ml)
• 5% glucose
• 6% Dextran in 0.9% sodium chloride (9 mg/ml)

The maximum recommended volume of sterile water for injectable preparations for each dose is 50 ml.

Incompatibilities
When TAZOPENIL is used concomitantly with another antibiotic (e.g., aminoglycosides), the substances must be administered separately. Mixing beta-lactam antibiotics with aminoglycosides in vitro may cause substantial inactivation of the aminoglycoside.
In case of intramuscular administration, piperacillin/tazobactam and aminoglycosides must be reconstituted and administered separately at different injection sites.
TAZOPENIL must not be mixed with other substances in the same syringe or infusion vial, as compatibility has not been established.
Due to chemical instability, TAZOPENIL must not be used with solutions containing sodium bicarbonate alone.
TAZOPENIL must not be added to blood products or albumin hydrolysates.

Overdose
Cases of overdose with piperacillin and tazobactam have been reported.
Most of the events experienced, including nausea, vomiting, and diarrhea, were reported at the usual recommended dosages. Patients may experience neuromuscular excitability or seizures if higher than recommended intravenous doses are administered (particularly in the presence of renal impairment).
Treatment should be supportive and symptomatic, based on the patient's clinical condition. Excessive serum concentrations of piperacillin or tazobactam may be reduced by hemodialysis.

Co-administration of Tazopenil with aminoglycosides
Due to in vitro inactivation of aminoglycosides by beta-lactam antibiotics, it is recommended that Tazopenil and aminoglycosides be administered separately. When concomitant therapy with aminoglycosides is indicated, Tazopenil and the aminoglycoside must be reconstituted and diluted separately.